Project Summary: Genomic Diversity and the Architectures of Adaptation and Incompatibility This research program addresses fundamental yet unresolved questions at the interface between genetic variation and evolutionary processes. In particular, it focuses on three interconnected research themes: (1) The Genetic Complexity of Adaptive Trait Evolution, (2) The Genetic Basis of Early Stage Reproductive Isolation, and (3) The Determinants of Genomic Diversity and Adaptive Potential. It fuses ambitious but cost-effective Drosophila experiments with novel approaches to the analysis of large genomic data sets. D. melanogaster offers critical advantages for this work. The global expansion of this species enables the study of adaptive trait differences, and partial reproductive isolation, between populations that diverged in the last ~10,000 years. Due to this recent time-scale, adaptive differences may be detected from genetic variation. The experimental efficiency of Drosophila allows the study of large lab populations across many generations. Its compact genome allows economical sequencing. Once relevant genes are found, functional confirmation and study are aided by a well-annotated genome and a wealth of genetic resources and transgenic tools. This research will bolster understanding of The Genetic Complexity of Adaptive Trait Evolution. Initial findings have suggested a portrait of adaptation that often begins with standing genetic variation, includes variants with larger effect sizes, and features variable genetic architectures among individuals. Proposed work will solidify and extend these inferences in multiple respects, including by launching scaled-up mapping studies for a wider range of adaptive traits, and pursuing previous hints of epistasis involving adaptive variants. Proposed work will also open up a promising new system for studying The Genetic Basis of Early Stage Reproductive Isolation. African and European D. melanogaster show evidence of incompatibilities impacting viability and reproduction, but these have received no genetic study. This research will deploy a combination of incompatibility mapping and population genomics to identify specific incompatibility genes for further study, and it will advance understanding of the genetic architecture of the earliest stages of reproductive isolation. Finally, this research will clarify The Determinants of Genomic Diversity and Adaptive Potential. This work will feature experimental and computational studies on the relative roles of neutral and adaptive genetic diversity in future adaptation, and the most relevant ways to quantify each. It will also investigate the relative importance of different types of natural selection in shaping genomic diversity, including by probing the utility of genetic differentiation between populations to separate the signals of positive and negative selection. Collectively, this research is highly consequential for basic evolutionary genetics. It also holds strong medical relevance in terms of the relevance of local adaptation and epistasis for the genetic basis of human disease and infertility, and for understanding the evolutionary dynamics of insect disease vectors.